original article risk factors associated with

ORIGINAL ARTICLE

Risk Factors Associated with Hypercoagulability in Type 2 Diabetes Mellitus Patients at Ndola Central

Hospital Zambia1* 2 3 3 2A. Mwambungu , T. Kaile , L. Korolova ,J. Kwenda , C. Marimo

1

Zambia. 2University of Zambia School of Medicine, Department of Pathology and Microbiology, P.O Box 50110, Lusaka,

Zambia.3University of Zambia School of Medicine, Department of Biomedical Sciences, P.O Box 50110, Lusaka, Zambia.

Ndola College of Biomedical Sciences, Department of Haematology and Blood Transfusion Medicine, PA Ndola,

*Corresponding authorA. MwambunguEmail: [email protected]

ABSTRACT

Background: Thrombosis, attributed to atherosclerosis,

is the leading cause of morbidity and mortality in patients

with diabetes mellitus. Pathogenesis of atherosclerosis in

diabetes mellitus is not entirely clear and conventional

risk factors such as smoking, obesity, blood pressure and

serum lipids fail to explain fully this excess risk. We set

out a cross-sectional study to determine the risk factors

and patient attributes that may predispose type 2 Diabetes

Mellitus (T2DM) patients to be in hypercoagulable state.

Methods: A structured questionnaire was used to capture

Age, Sex, duration of diabetes mellitus and knowledge on

T2DM of study participants. Body weight and height

were also measured and BMI calculated.VWF,

Cholesterol, and Glycated haemoglobin were measured

in 213 T2DM patients. VWF was used as a proxy marker

for hypercoagulability in T2DM patients. Participants

with VWF of >2.0 IU/ml plasma concentration were

regarded to be in hypercoagulable state.

Results: Chi-square analysis revealed that

hypercoagulability in T2DM patients was associated with

Age (P=0.001), Sex (P=0.000), glycaemic control

(P=0.003), duration of diabetes (P=0.000), BMI

(P=0.000) and knowledge on type 2 diabetes mellitus

(P=0.001). In multivariate analysis after adjusting for

confounders, knowledge on T2DM was not

independently associated with hypercoagulability AOR

being 1.00(CI 95% 0.80-2.20). However Age, sex,

glycaemic control, duration of diabetes and BMI were

found to be independent r i sk fac tors fo r

hypercoagulability in T2DM patients giving AOR of

1.45(95%CI[1.19-3.16]), 4.42 (95% CI [2.77-10.63]),

6.12 (95% CI 2.27-8.36) 5.28(CI 95% 3.01-8.21) and

1.05(95% CI 0.75-2.86) respectively.

Conclusion: Age, Sex, poor glycaemic control, duration

of diabetes and obesity should be taken into account in the

management of T2DM patients as these variables are

independent risk factors of hypercoagulability in T2DM

patients.

INTRODUCTION

The incidence of Type 2 Diabetes Mellitus (T2DM) is

rapidly growing in the world. In 1985, an estimated 30

million people suffered from this chronic disease, which,

by the end of 2006, had increased to 230 million,

representing 6% of the world population. Of this number,

80% is found in the developing world (1). An increase of

as high as 146% is predicted to occur in developing

countries, while the increase would only be 47% in

developed countries. This means that developing

countries will contribute 77.6% of the total number of

diabetic patients in the world by the year 2030 (2). A

population based survey conducted in Zambia found the

prevalence of type 2 Diabetes Mellitus to be 2.1 % among

males and 3.0% among females (3). This rapidly growing

prevalence among developing countries is primarily as a

result of demographic and epidemiological transition

occurring in these countries as a consequence of

urbanization, industrialization and globalization (4).

Key words: Hypercoagulability, Type 2 diabetes mellitus, VWF, Glycaemic control, BMI

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Medical Journal of Zambia, Vol. 41, No. 2: 70 - 80 (2014)

Thrombosis is the leading cause of morbidity and

mortality in patients with diabetes mellitus. The

thrombosis is attributed to atherosclerosis. The

pathogenesis of the atherosclerosis in diabetes mellitus is

not entirely clear and conventional risk factors such as

smoking, obesity, blood pressure and serum lipids fail to

explain fully this excess risk. Fibrin deposition is an

invariable feature in atherosclerotic lesions. Therefore,

disturbances of haemostasis leading to accelerated fibrin

formation (hypercoagulability) and delayed fibrin

removal (impaired fibrinolysis) may contribute to the

development of atherosclerosis.

Several mechanisms contribute to the diabetic

prothrombotic state, such as endothelial dysfunction,

coagulative activation and platelet hyper-reactivity. In

particular, diabetic platelets are characterized by

dysregulation of several signaling pathways leading to

enhanced adhesion, activation and aggregation (5). These

alterations result from the interaction between

hyperglycemia, insulin resistance, inflammation and

oxidative stress. Many studies have shown a variety of

diabetes mellitus-related abnormalities in hemostasis and

thrombosis. Venous thrombosis has also been found to

occur more frequently in diabetics (6). Hypofibrinolysis

is well established in T2DM and characterized by

elevated levels of plasminogen activator inhibitor-1 (PAI-

1) as well as prolonged clot lysis time. The higher PAI-1

levels can be observed in the more poorly controlled Type

2 Diabetes Mellitus (T2DM) patients (7).

Pandolfi et al., (2007) reported an increase in the number

of T2DM patients in hypercoagulable state, indicating

that there is an increase in Type 2 Diabetes Mellitus

patients at risk of thrombosis (6). The reason for this

increase in hypercoagulability among T2DM patients is

not known but may be multifactorial. It could be due to

poor glycaemic control, aging, obesity, unhealthy diet

and sedentary life styles among T2DM patients.

The aim of this study was to determine risk factors and

patient attributes associated with hypercoagulability in

T2DM patients. These include age, history of diabetes,

poor glycaemic control and lack of awareness about

Diabetes Mellitus and its complications. It is very

cardinal that these factors are investigated so as to have

data that will help clinicians to identify type 2 diabetic

patients at risk of developing thrombosis and institute

early treatment.

PATIENTS AND METHODS

This cross-sectional study was conducted at Ndola

Central Hospital (NCH), a third level referral hospital for

Copperbelt and the Northern part of Zambia. It is located

in Ndola, the provincial headquarters of the Copperbelt

Province. The hospital has a bed capacity of 851.

The study included Type 2 Diabetes Mellitus patients

attending Ndola Central Hospital Out-patient Department

(OPD) Diabetic clinic between November 2012 to May

2013. The total number of type 2 diabetes mellitus

patients recruited was 213 and convenience sampling was

used to recruit the study participants.

Selection criteria

Inclusion criteria:

The study included male and female Type 2 Diabetes

Mellitus patients above the age of 18 years.

Exclusion criteria

Part ic ipants who had a his tory of venous

thromboembolism or known inherited coagulation

disorders, Cancer and hyperthyroidism were excluded

from the study. Others excluded include, those who were

Pregnant, Recently undergone surgery, Patients taking

standard anticoagulant treatment, less than 18 years and

those not willing to consent.

Data collection

A structured questionnaire was used to collect

information from the participants. The information

collected included Demographic information, Physical

measurements (Height and Weight), Levels of awareness

about type 2 Diabetes Mellitus risk factors, management,

complications and duration of type 2 Diabetes mellitus

disease for each participant.

The WHO STEPs surveillance training and practical

guide recommends that physical measurements be taken

in the following order: Height, Weight and Blood

Pressure. Therefore these measurements were taken in

that order (3).

Participant' height was measured in meters using the seca

Brand 214 Portable stadiometer. It was measured without

the participants wearing foot or head gear. and it was

recorded in meters. Participants' weight was measured

using the Heine Portable Professional Adult Scale 737

and was recorded in kilograms.

71


Body Mass Index (BMI) was calculated by dividing the

participants' weight in kilograms by the square of height

in meters.

Assays

Good Laboratory Practice (GLP) principles according to

Zambia Ministry of health laboratory quality manual was

observed to ensure uniformity, consistency, reliability

and reproducibility of all the laboratory test results that

were produced in this study. Venous blood collection was

done using the evacuated blood collection system. 3 ml of

venous blood was collected for each test.

Venous blood for total cholesterol estimation was

collected in plain containers. The samples were

centrifuged within 4 hours of blood collection and serum owas separated from the red cells and frozen at -30 C for

subsequent analysis. Total Cholesterol was determined

using the Humalyser 2000 semi-automated clinical

chemistry analyser. The cholesterol liquicolor reagents

manufactured by Human Gesellschaft of Germany were

adapted for use on the Humalyser 2000 analyser. The

method used was the Cholesterol Oxidase─Phenol-4-

aminophenazone (CHO-PAP) method. The principle of

this method is based on Flegg and Richmond method (8).

Cholesterol levels were classified as normal if less than or

equal to 5.2 mmol/l and raised if greater than 5.2 mmol/l.

Three (3) ml of venous blood for vWF was collected from

each of the study participants in sodium citrate containers

and centrifuged at 1500g for 15 minutes. Plasma was then

separated and transferred into siliconized glass tubes and

stored at 4C in a fridge until analysis. VWF was

determined by the Human ELISA kit manufactured by

Abnova of USA. Plasma VWF concentration results were

reported in International units/ml (IU/ml).The reference

range for plasma concentration of vWF is 0.6 to 2.0

IU/ml. Any result above 2.0 IU/ml was regarded as being

in hypercoagulable state.

Venous blood collected in EDTA containers was used for

glycated Haemoglobin (HbA1C) estimation. Bio-Quant

Glycated Haemoglobin (HbA1C) Enzymatic assay kit

produced by BioSupply of United kingdom was used to

determine HbA1C in whole blood. This was measured

primarily to identify the average plasma glucose

concentration over the past 3-4 months and hence indirect

indicator of glycaemic control in Type 2 Diabetes

Mellitus patients.

Hypercoagulation in Type 2 Diabetes Mellitus patients

was determined by estimating vWF and the results

obtained were compared with the potential risk factors for

hypercoagulation such as age, sex, glycaemic control,

duration of type 2 Diabetes Mellitus and awareness of

type 2 diabetes Mellitus risk factors and complications.

The VWF, which was a continuous variable in SPSS, was

recoded so as to categorise the VWF results into two

categories; those who had VWF of greater than 2.0 IU/ml

were categorized as hypercoagulable and those whose

VWF results were ≤ 2.0IU/ml were regarded as normal.

Thereafter a chi-square test of independence was done to

determine the proportion of hypercoagulability in type 2

diabetes mellitus patients and control subjects.

Age of type 2 Diabetes mellitus patients was categorized

and each category's frequency of hypercoagulability

(vWF > 2.0 IU/ml) was determined and compared among

different categories to determine if the differences were

statistically significant.

Glycated haemoglobin was used as an indirect measure of

glycaemic control in type 2 Diabetes Mellitus patients.

Glycated haemoglobin of less than or equal to 7% was

regarded as good glycaemic control, while HbA1C of

greater than 7% was regarded as poor glycaemic control.

Using the chi-square test the frequency of

hypercoagulability was compared between those with

good glycaemic control (HbA1c ≤ 7%) and poor

glycaemic control (HbA1c >7.0%) and analyzed for any

significance difference in hypercoaugulation. Logistic

regression was used to obtain the odds ratios and

determine the strength of association between glycaemic

control and hypercoagulation.

A general questionnaire was used to investigate the level

of awareness about Diabetes Mellitus risk factors,

complications and management among type 2 Diabetes

Mellitus patients. Participants were asked to mention the

risk factors, complications and management of type 2

Diabetes Mellitus. Participants who mentioned 2 or less

risk factors/complications and less than 2 ways of

managing type diabetes mellitus, were deemed to have

inadequate knowledge and those who mentioned 3 or

more risk factors/complications and more than 2 ways of

managing type 2 diabetes mellitus were deemed to have

adequate knowledge about type 2 diabetes mellitus risk

factors/complications and management of type 2 diabetes

mellitus. The proportion of hypercoagulability between

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those with adequate knowledge and inadequate

knowledge was analysed statistically using the chi-square

and determined any significance difference between these

two groups. Logistic regression was used to determine the

strength of association between hypercoagulability and

level of knowledge about type 2 diabetes mellitus risk

factors and complications.

Data for duration of type 2 diabetes Mellitus for each

patient was obtained from the questionnaire. The duration

was categorized into ≤5 years, 5 to 10 years and > 10

years. Using the chi-square test, the proportion of

hypercoagulability was compared among the three

categories and determined whether the differences in the

proportions were statistically significant. Logistic

regression was used to determine the strength of

association between duration of type 2 diabetes mellitus

and hypercoagulation.

Ethical considerations

This study was performed under a protocol that was

reviewed and approved by the University of Zambia-

Biomedical Research Ethics Committee (UNZA-BREC).

Written permission was obtained from the Permanent

Secretary in the Ministry of Health as well as from the

Senior Medical Superintendent of Ndola Central

Hospital. All the prospective participants in this study

were informed about the study, privileges and right to

participation. The purpose of the study was thoroughly

explained to the participants and those that declined to

participate in the study were not forced, but were assured

of their protected privileges and rights to treatment.

Privacy and confidentiality was maintained. The names of

the respondents did not appear anywhere on the forms

instead codes were used on the forms. The forms were

kept in lockable cabinets and no one apart from the

researcher had access to the cabinets. Data on the

computer was pass-word protected such that access was

limited to only the researcher. The respondents were thus

assured of utmost confidentiality. Only qualified medical

professionals such as nurses and laboratory staff were

involved in the collection of venous blood samples from

study participants. Consenting patients and control

participants were made to sign the consent form before

being enrolled into the study.

Data analysis

The Statistical Package for Social Science (SPSS version

16) was used to analyse the results statistically. Analysis

of distribution was made using the Kolmogoroff-

Smirnoff test. All the parameters were normally

distributed and hence reported as the mean +/- standard

deviation. The significance of the differences between

patients and controls for normally distributed parameters

were determined using the independent samples T-test for

continuous variables and Chi-square test for categorical

variables. Risk factors and patient attributes associated

with hypercoagulability in type 2 Diabetes Mellitus were

determined by Binary Logistic regression analysis. Odds

ratios and their 95% confidence intervals are reported.

RESULTS

A total of 213 T2DM patients aged 21-83 years

participated in the study with the majority of participants

[80 (37.6%)] being in the range of 51-60 years. The mean

age was 45 years old (SD 4.31). Figure I shows that the

proportion of T2DM patients who had good glycaemic

control was lower [100(46.9%)] than those who had poor

glycaemic control [113(53.1%)]. The proportion of

T2DM patients who had adequate knowledge about the

risk factors and complications of T2DM was slightly

higher [108(50.7%)] than those who had inadequate

knowledge [103(49.3%)]. The proportion of participants

who were obese [62(29.2%)] was lower than those who

had a normal BMI [84(39.4%)]. A higher proportion of

participants had T2DM condition for more than 10 years

[95(44.6%)] than those who have had the condition for

less than 5 years or between 5-10 years [69(32.4%)] and

[49(23.0%)] respectively.

Table I and figure II reveals that at the 5% level the

proportions of subjects that were hypercoagulable

differed significantly among the 21-30, 31-40, 41-50, 51-

60 and > 60 age groups in T2DM Patients, P=0.001. The

proportion of T2DM Patients who were hypercoagulable

was higher in the age range of 51-60 years and above 60

years [60(93.8%)] and [18(94.7 %)] respectively. This

shows that there was a significant correlation between age

and hypercoagulation.

At 5% level the proportions of male T2DM patients who

were in hypercoagulable state [38(40.9%)] was lower

than in female T2DM patients [88(73.3%)]. This .difference was significant P=0.000 (Table I and Figure

III).

Table I and figure IV shows that the proportion of type 2

diabetes mellitus patients who were hypercoagulable was

higher in those with poor glycaemic control [92(81.4%)]

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Variable Total N % P-Value

Age (years)

21-30 10 0 0 0.001

31-40 40 2 5.0

41-50 80 46 57.5

51-60 64 60 93.8>61 19 18 94.7

Gender

Male 93 38 40.9 0.000

Female

120 88 73.3

Glycaemic control

Good

100 34 34.0 0.003

Poor

113 92 81.4

Duration of type 2 Diabetes mellitus

Less than 5 years

67 14 20.9 0.000

5 to 10 years

49 22 44.9

Greater than 10 years

97 90 92.8

Body Mass Index Normal

84 28 33.3 0.000

Overweight

67 42 62.7

Obese

62 56 90.3

Knowledge on type 2 Diabetes Mellitus

Adequate Knowledge 108 48 44.4 0.001

Inadequate knowledge 105 78 74.3

Table I: Proportion of type 2 diabetes mellitus patients with hypercoagulability according to patient attributes

Univariate Multivariate

Factor OR 95% C.I AOR 95% C.I

Sex

Male®

Ref

Ref

Female

3.98

2.23-7.10 4.42 2.77-10.63

Age (Years) 21-30®

Ref

Ref

31-40

1.00

0.15-2.62 1.16 0.36-4.77

41-50

2.12

0.58-4.23 1.58 0.41-6.02

51-60

2.61

1.20-4.80 2.53 1.21-4.25

≥61

2.66

1.05-4.87 1.45 1.19-3.16

Glycaemic Control

Good®

Ref

Ref

Poor

7.50

4.53-10.95 6.12 2.27-8.36

Duration

<5 years®

Ref

Ref

5-10 years 3.08 1.37-6.97 2.20 1.07-4.44

>10 years 8.67 5.48-11.85 5.28 3.01- 8.21

Body Mass Index

Normal® Ref Ref

Overweight 1.52 1.06-4.32 1.05 0.75-2.86

Obese 5.33 2.26-11.48 4.54 2.88-10.59

Knowledge about Type 2 diabetes Mellitus

Adequate knowledge® Ref Ref

Inadequate Knowledge 3.48 1.96-6.18 1.00 0.80-2.20

OR: odds ratio; AOR: adjusted odds ratio; ®: Reference group

Table II: Univariate and multivariate regression results: likelihood of hypercoagulability among type 2 diabetes mellitus patients based on patient attributes

Figure I: Demographic and other attributes of type 2

diabetes mellitus

DM: Diabetes Mellitus

21-30 years 31-40 years 41-50 years 51-60 years Greater than 60 years

Age

Num

ber o

f par

ticip

ants

0

10

20

30

40

50

60

Figure II: Age as a function of hypercoagulability (VWF>

2.0 IU/ml)

Figure III: Gender as a function of hypercoagulability (VWF 2.0 > IU/ml)

Vonwillebrands factor

NormalHyprcoagulable



74


Vonwillebrands factorNormalHyprcoagulable

Figure IV: Glycaemic control as a function of

hypercoagulability (VWF >2.0 IU/ml)

Figure V: Duration of Diabetes Mellitus as a function

of hypercoagulabilty (VWF> 2.0 IU/ml)



Figure VI: Knowledge about type 2 Diabetes Mellitus risk factors, complications and management as a function of hypercoagulability. (VWF >2.0 IU/ml)

Figure VII: BMI as a function of hypercoagulability (VWF > 2 IU/ml)



Vonwillebrands factorNormalHyprcoagulable

75


as compared to those with good glycaemic control

[34(34.0%)]. The difference was significant, P=0.003.

Table I and figure V shows that hypercoagulability in

Type 2 Diabetes Mellitus patients was dependent on the

duration of the disease. Those who had the disease for

over 10 years had a higher proportion of

hypercoagulability [90(92.8%)] than those who had it in

less than 5 years [22(44.9%)]. P=0.000. Hence there was

a significant correlation between duration of T2DM and

hypercoagulability.

The proportion of type 2 diabetes mellitus patients who

were hypercoagulable was lower in those who had

adequate knowledge about the risk factors of T2DM

[48(44.4%)] than in patients who had inadequate

knowledge [78(74.3%)]. This difference was statistically

significant. P=0.000. (Table I and figure VI)

Table I and figure VII shows that hypercoagulability in

T2DM patients was dependent on body mass index. The

proportion of obese patients who were hypercoagulable

was significantly higher 56(90.3%)] than those who had a

normal body mass index [28(33.3%)]. P=0.000. Hence

there was a significant correlation between body mass

index of T2DM and hypercoagulability.

Logistic regression was used to determine the risk factors

associated with hypercoagulability in T2DM patients.

Table II reports the results of multivariate regression

analysis revealing patient attributes that were also

independent risk factors for hypercoagulability in type 2

diabetes mellitus patients. Sex was significantly

associated with hypercoagulability. Type 2 diabetes

mellitus female patients were 3.98(95% CI [2.23-7.10])

times more likely to be hypercoagulable than the male

patients. Even after adjusting for confounders such as

obesity, hypercholesterolemia and hypertension, the odds

of female T2DM patients being hypercoagulable was still

significant AOR being 4.42 (95% CI [2.77-10.63])

In an unadjusted model, Age was significantly associated

with hypercoagulability in type 2 Diabetes Mellitus

patients. Participants aged 51-60 years and those aged 61

years and above were more likely to be hypercoagulable

than those in the age range of 21-30 years OR 2.61(95%

CI[1.20-4.80]) and 2.66(95%CI[1.05-4.87) respectively.

Even after adjusting for cofounders participants whose

age was between 51-60 years and above 61 years were

more at risk of hypercoagulability than those in the age

range of 21-30 years giving an AOR of 2.53(95%

CI[1.21-4.25]) and 1.45(95%CI[1.19-3.16])

respectively.

In an unadjusted model, type 2 diabetes mellitus patients

who had poor glycaemic control 53.1% (OR=7.50; 95%

CI [4.53-10.95]) were more likely to be hypercoagulable

than those who had good glycaemic control. The odds of

being hypercoaugulable were still high even after

adjusting for age, hypercholesterolemia and obesity,

giving an AOR of 6.12 (95% CI 2.27-8.36).

Duration of type 2 diabetes mellitus was significantly

associated with hypercoagulability. Participants who had

the disease between the duration of 5 – 10 years and those

who have had the disease more than 10 years were

OR=3.08 (95% CI 1.37-6.97) and OR= 8.67 (95% CI

5.48-11.85) times more likely to be hypercoagulable than

those who had the disease for the duration of less than 5

years. The odds of being hypercoaugulable was still high

even after adjusting for age, hypercholesterolemia and

obesity, giving an AOR of 2.20(95% CI 1.07-4.44) and

5.28(CI 95% 3.01-8.21).

Body Mass Index was significantly associated with

hypercoagulability in type 2 diabetes mellitus patients.

Participants who were overweight were 1.52(95% CI

1.06-4.32) more likely to be hypercoagulable than those

whose BMI was normal. The odds of being

hypercoagulable in participants who were obese were

5.33(95% CI 2.26-11.48). After adjusting for cofounders

the odds of being hypercoagulable in the obese group was

4.54(95% CI 2.88-10.59). In the overweight group the

odds of hypercoagulability became 1.05(95% CI 0.75-

2.86). The null value is 1, and because this confidence

interval does include 1 in adjusted model, the result

indicates a statistically insignificant difference in the

odds of overweight and normal individuals in terms of

hypercoagulability.

In univariate analysis type 2 diabetes mellitus patients

who had inadequate knowledge on the risk factors,

complications and management of type 2 diabetes

mellitus were 3.48 more likely to be hypercoagulable

than those with adequate knowledge OR 3.48(CI 95%

1.96-6.18). However after adjusting for glycaemic

control, age, hypercholesterolemia and obesity, the odds

of hypercoagulability was the same in those with

adequate knowledge about the risk factors and

complications and those who had inadequate knowledge,

AOR being 1.00(CI 95% 0.80-2.20).

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DISCUSSION

This research revealed that patients aged 51 years and

above were at risk of hypercoagulability than those who

were below 51 years old. These results are consistent with

the findings of past studies. Soltani and colleagues

reported a significant correlation between age and

hypercoagulability in T2DM patients (9). These results

accords that of Zhaolan et al.,(2010), who reported a

s i g n i f i c a n t a s s o c i a t i o n b e t w e e n a g e a n d

hypercoagulation in type 2 diabetes mellitus patients

(10). The results are further supported by Khattaba et

al.,(2010) who reported that older type 2 diabetes

mellitus patients were more likely to be hypercoagulable

than the younger patients (11). The risk of

hypercoagulability with increasing age could be

attributed to the changes that occur to the vascular system

sclerosis as a result of aging thus tilting the scale to

hypercoagulability in older patients.

In the current study, the proportion of female T2DM

patients who were in hypercoagulable state was higher

than the male T2DM patients. Logic regression analysis

showed that women were four times at risk of

hypercoagulability than the male patients (Fig IV, Table I

and II). This findings was consistent with that reported in

Egypt by Soliman G., (2005), who reported that female

T2DM patients were more hypercoagulable than male

patients by finding significantly higher fibrinogen levels

in female T2DM patients than male patients (12). higher

plasma fibrinogen level in diabetic females than diabetic

males (13). On Similar results were reported by Soedama

et al., (2008), The results are also in concomitant with that

of Screiber et al., (2005) reported that Women are more

hypercoagulable than men early after injury in a study

conducted to determine the course of coagulation after

injury and to determine whether there is a gender

difference (13). The results of this study further accords

that of Michael W et al., (2002), who found significantly

higher FVII: C, Vonwillebrands and PAI-1 levels in

women than in men with T2DM(14). The finding of

higher PAI-1 and vWF levels in diabetic women

therefore may indicate an important sex-specific

interference in the haemostatic system by diabetes that

could increase vascular risk (14). A mechanism

independent of insulin resistance by which female sex

could be associated with higher vWF, FVIII: C and PAI-1

levels in T2DM is not clear. Differences caused by sex

hormone levels do not explain the findings. In women

higher estrogen levels are associated with lower PAI-1

levels while in healthy postmenopausal women not

receiving estrogen replacement, PAI-1 levels are no

higher than in men of the same age (15) . In the present

study no assessment was made of sex hormone levels.

Investigation of the relationship among female hormonal

status, haemostatic variables, and the features of insulin

resistance in premenopausal and postmenopausal T2DM

women may help in the evaluation of the importance of

estrogens and vWF and PAI-1 in thrombotic development

in women with T2DM.

In this study poor glycaemic control was associated with

hypercoagulability in T2DM.These results are consistent

with Chantal et al., (2010), who also found significant

associat ion between glycaemic control and

hypercoagulability (16). The results also accords that of

Osende et al., (2008), who reported a correlation between

improved glycaemic control and blood thrombogenicity

(17). Poor glycaemic control may lead to

hypercoagulability because of the effects of glucose on

the endothelium. Long term high glucose levels damage

the endothelium by accelerating glycosylation of proteins

and lipids to generate advanced glycation end products

(AGEs) (18). AGEs accumulate in the vessel wall, where

they may directly disturb cell structure and function.

Furthermore, the receptor for AGEs (RAGE) activation

on endothelial cells inhibits nitric oxide (NO)

biosynthesis by endothelial NO synthase (eNOS) down

regulation, with increased generation of ROS.ROS as a

negative effect on NO by forming the highly oxidant

peroxynitrite ion, which in turn uncouples eNOS to

produce superoxide anion and asymmetr ic

dimethylarginine (ADMA) , an endogenous inhibitor of

eNOS. NO is important in haemostasis because it inhibits

platelet aggregation therefore a reduction of NO may lead

to unregulated platelet aggregation (19).

In this study a good statistically significant correlation

was found between the prevalence of hypercoagulability

and the duration of diabetes mellitus that was consistent

with findings of other studies. Participants who had the

disease for a period of 10 years and above were more

likely to be hypercoagulative than those who had it for

duration of less than 5 years. Infact the odds of being

hypercoagulable in T2DM patients increased with the

increase in the duration of diabetes. Chantal et al., (2010)

77


and Barbic et al., (2010) reported a significant correlation

between hypercoagulability and the duration of diabetes

(16,20). The reason for this correlation may be due to the

effects of hyperglyceamia on the endothelium over a

prolonged period of time. Damage to the endothelium

tend to increase with the increase in the duration of T2DM.

In chi-square test of independence the proportion of

individuals who were hypercoagulable was significantly

higher in individuals who had inadequate knowledge

about the risk factors and complications of T2DM. In the

univariate analysis the odds of hypercoagulability in

participants who had inadequate knowledge about T2DM

risk factors and complications was higher than in those

who had adequate knowledge. In the multivariate analysis

after adjusting for glycaemic control the adjusted odds

ratio was 1 indicating that the risk of hypercoagulability in

those who had adequate knowledge and inadequate

knowledge about the risk factors and complications of

T2DM was the same. This is inconsistent with the results

obtained by Blankenfeld et al., (2006), who reported that

the existence of diabetes related complications was a

significant predictor of poor knowledge in T2DM patients

(21). However in this study Blankenfeld and colleagues

did not adjust for glycaemic control. This may be the

reason why there was such a discrepancy. Blankenfeld et

al., (2006) further reported that patients who have

inadequate knowledge about the risk factors and

complications of the disease are more likely not to adhere

to treatment or may be inconsistent in going to the

Hospital for review so as to have the glucose levels

checked (21). The results are also in contrast with Ulvi et

al., (2009) who reported a positive correlation between

hypercoagulability and levels of knowledge about the risk

factors and complications of T2DM patients among the

rural community in Pakistan. T2DM patients with

inadequate knowledge about the risk factors,

complications and management of diabetes are less likely

to understand why glucose levels should be monitored and

hence usually tend to have poor glycaemic control and

consequently increased hypercoagulability. Patients with

adequate knowledge on the other hand may be very

careful with their lifestyles because they know the

complications that may occur if they don't adhere to

proper treatment and risk free life style and hence able to

have better glycaemic control (22).

In this study obesity was significantly associated with

hypercoagulability in T2DM patients . T2DM patients

who were obese were more likely to be hypercoagulable

than the non-obese T2DM patients. These results are

consistent with most of the past studies. Muthu et al.,

(2009), Soltani et al., (2011) and Kozek et al., (2004)

found increased hypercoagulability with increased levels

of cholesterol (9, 23, 24). Obesity was first proposed to be

a risk factor for the development of atherosclerosis and

T2DM over 40 years ago (24). Metabolic alterations

accompanying the visceral distribution of fat lead to

arterial hypertension, dyslipidemia, insulin resistance and

subsequently to T2DM. This phenomenon is associated

not only with classical atherosclerotic risk factors but also

with coagulation and fibrinolysis abnormalities (25).

Hypercoagulation in obesity is thought to be caused

primarily by the synthesis of factors activating

coagulation and inhibiting fibrinolysis (for example

factor VII activator and the fibrinolytic inhibitor PAI-1) in

adipose tissue(24). Hemostatic abnormalities may also

result from the synthesis in adipose tissue of cytokines

that are mediators of inflammation and insulin resistance,

such as interleukin 6 and TNF-alpha. In addition to this

direct effect, the metabolic and lipid alterations that

accompany obesity and T2DM are likely to indirectly

influence coagulation properties in these patients.

Hypercholesterolemia, obesity and hypertension are

interrelated. Both obesity and hypercholesterolemia have

been implicated in the development of T2DM and both

are also associated with hypercoagulation. Studies have

shown that raised plasma insulin levels with insulin

resistance appears to be an atherogenic factor. Insulin

stimulates cholesterol synthesis in smooth muscle cells

and macrophages of the arterial walls and also stimulates

the proliferation and migration of smooth muscle cells.

Prospective data is needed to clarify whether these factors

preceded T2DM or they are a consequence of the disease

(26).

CONCLUSION

The main aim of this study was to determine the risk

factors associated with hypercoagulability in T2DM

patients at Ndola Central Hospital. The variables that

were found to be independent risk factors of

hypercoagulability among T2DM patients were Age, sex,

duration of T2DM, obesity, and poor glycaemic control.

78


ACKNOWLEDGEMENT

I wish to express my sincere gratitude to management at

Ndola Central Hospital.

ABREVIATIONS USED

ADMA:Asymmetric dimethylarginine; AGEs:Advanced

Glycation End Products; AOR:Adjusted Odds

Ratio;

BMI: Body Mass Index;

GLP: Good Laboratory Practice;

HBAIC: Glycated Haemoglobin;

NCH: Ndola Central Hospital;

NO: Nitric Oxide;

OPD: Outpatient Department;

OR: Odds Ratio;

PAI: Plasminogen Activator Inhibitor;

ROs: Reactive Oxygen Species;

T2DM: Type 2 Diabetes Mellitus;

UNZA-BREC: University of Zambia Biomedical

Research Committee;

VWF: Vonwillebrands' factor;

WHO: World Health Organisation.

REFERENCES

1. Roglic G, Unwin N, Bennett PH, Mathers C,

Tuomilehto J, Nag S, et al . The burden of mortality

attributable to Diabetes Mellitus: Realistic estimates

for the year 2000. Diabetes Mellitus Care 2005;

28:2130–5.

2. Mario Azevedo and Sridevi Alla. Diabetes Mellitus in

Sub-Saharan Africa: Kenya, Mali, Mozambique, Nigeria, South Africa and Zambia. Int J Diabetes

Mellitus Dev Ctries. Oct-Dec 2008; 28(4): 101–108.

3. Nsakashalo Senkwe et al. Combined prevalence of

impaired glucose level or Diabetes Mellitus and its

correlates in Lusaka urban district, Zambia:

Population based survey. International Archives of

Medicine .2011; 4:2

http://

4. Frank B. Globalization of Diabetes: The role of diet,

lifestyle, and genes Diabetes Care vol. 2011; 34 (6)

1249-1257.

5. Vazzana N, et al, Diabetes Mellitus and thrombosis,

Thromb Res 2011; 129:371–377.

6. Pandolfi A andDe Filips EA. Chronic hyperglycemia

and nitric oxide bioavailability play a pivotal role in

pro-atherogenic vascular modifications. Genes Nutr

2007; 2:195- 208.

www.intarchmed.com/content/4/1/2

7. Lemkes BA, Hermanides J, Devries JH, Holleman F,

Meijers JC, Hoekstra JB. Hyperglycemia: a

prothrombotic factor? J Thromb Haemost.

2010;8:1663–9.

8. Human Gesellschaft fur Biochemica und Diagnostica

mbH Max-Planck-Ring 21 . 65205 Wiesbaden .

Germany e-Mail

9. Soltan and Dayer R. Coagulation Factors Evaluation

in NIDDM Patients. AmericanJournal of

Biochemistry and Molecular Biology. 2011 ;( 3): 244-

254.

10. Zhaolan et al. Prevalence of chronic complications of

type 2 Diabetes Mellitus in outpatients. Health and

quality of life outcomes. 2010; 8:62.

11. Khattaba Maysaa, Yousef S. Khaderb, C, Abdelkarim

Al-Khawaldehd, Kamel Ajlounid Factors associated

with poor glycemic control among patients with Type

2 diabetes Journal of Diabetes and Its Complications

2010; 24 84–89

12. Soliman G. Abnormalities in Plasma Concentration

o f L ip id s and F ib r inogen o f Egyp t i an

Microalbuminuric NIDDM Type2 Diabetic Patients.

The Egyptian Journal of Hospital Medicine 2005;

21:66-81.

13. Schreiber MA, Differding J, Thorborg P.

Hypercoagulability is most prevalent early after

injury and in female patients. J Traum. 2005 Mar;

58(3):475-80; discussion 480-1.

14. Michael W. Mansfield; Daniella M. Heywood; Peter

J. Grant . Sex Differences in Coagulation and

Fibrinolysis in White Subjects with Non–Insulin-

Dependent Diabetes Mellitus Arteriosclerosis,

Thrombosis, and Vascular Biology. 2002; 16: 160-

164.

15. Gebara OC, Mittleman MA, Sutherland P, Lipinska I,

Matheney T, Xu P, Welty FK, Wilson PW, Levy D,

Muller JE, Tofler GH (2008) Association between

increased estrogen status and increased fibrinolytic

potential in the Framingham Offspring Study.

Circulation 2008; 91:1952-1958.

16. Chantal J. N. Verkleij. Clinical and Applied

Thrombosis/Haemostasis. The Haemostatic System

in Patients with Type 2 Diabetes with and without

Cardiovascular Disease Clin Appl Thromb. 2010; vol.

17 no. 6 E57-E63.

17. Osende JI, Badimon JJ, Fuster V, Herson P, Rabito P,

Vidhun R, et al. Blood thrombogenicity in type 2

diabetes mellitus patients is associated with

[email protected]

79


http://www.ncbi.nlm.nih.gov/pubmed?term=%22Makanza%20ED%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Mungofa%20S%22%5BAuthor%5D

glycaemic Control. J Am Coll Cardiol 2008;

38:1307–12.

18. Santilli F, Vazzana N, Bucciarelli LG, Davì G. Soluble

forms of RAGE in human diseases: clinical and

therapeutical implications. Curr Med Chem 2009;

16:940–52.

19. Devangelio E, Santilli F, Formoso G, Ferroni P,

Bucciarelli L, Michetti N. Soluble RAGE in type 2

diabetes: association with oxidative stress. Free Radic

Biol Med, 2007; 43:511–8.

20. Babic N. Coagulation factor VIII in diabetic patients.

Med Glas komore Zenicko. 2011; 8:134-139.

21. Blankenfeld H, Mielck A, Schumm-Draeger PM,

Siegmund T. How much do inpatient treated diabetics

know about their disease? : Gesundheitswesen. 2006;

68(8-9):557-65.22. Ulvi Osman Saleem, Raheel Yousaf Chaudhary, Tanya

Ali, Rizwan A. Investigating the awareness level

about Diabetes Mellitus and associated factors in Tarlai (Rural Islamabad): J Pak Med Assoc 2009; Vol. 59, No. 11.

23. Muthu S.S, chaturved N. Relationship between plasma sialic acid and fibrinogen Concentration and incident of micro- and macrovascular complications in type 1 diabetes. Diabetologia 2009; 51:493-501.

24. Kozek Elzbieta , Barbara Katra, Maciej Malecki, and Jacek Sieradzki (2004) Visceral Obesity and Hemostatic Profile in Patients with Type 2 Diabetes: The Effect of Gender and Metabolic Compensation Rev Diabetes Stud. 2004; 1(3): 122–128.

25. Sakkinen PA, Wahl P, Cushman M, Lewis MR, Tracy RP Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol. 2009; 15:897–907.

26. Fein FS. Heart diseases in diabetes Cardiavasc.Rev Rep 2002;3:877-93

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